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Rosenblat M.,The Rappaport Family Institute for Research in the Medical science | Volkova N.,The Rappaport Family Institute for Research in the Medical science | Aviram M.,The Rappaport Family Institute for Research in the Medical science
Atherosclerosis | Year: 2010

Objective: To examine whether the beneficial effects of PJ consumption by mice on their macrophages are mediated via PJ-induced increment in serum paraoxonase 1 (PON1) activity and/or in macrophage PON2 expression. Methods and results: We performed studies in peritoneal macrophages (MPM) from C57BL/6 control mice, or from PON1KO mice, or from PON2KO mice that consumed PJ (200 μg of gallic acid equivalents/mouse/day, for 1 month period).PJ consumption by C57BL/6 mice resulted in a significant increment, by 36% in serum PON1 catalytic activities, and upregulated MPM PON2 expression.In MPM from C57BL/6 or from PON1KO mice that consumed PJ, the extent of cell-mediated LDL oxidation was decreased by 22%, and that of cellular superoxide release by 20-26%. In contrast, PJ consumption by PON2KO mice resulted in a minimal inhibitory effect on macrophage oxidative stress by only 4-9%. Unlike PJ antioxidative effects in MPM, PJ anti-atherogenic effects on MPM cholesterol and triglyceride metabolism were similar in all mice groups that consumed PJ. After PJ consumption, cellular cholesterol content was decreased by 14-19%, and this could be attributed to a significant inhibition in MPM cholesterol biosynthesis rate by 20-32%, and/or to stimulation of HDL-mediated cholesterol efflux from the cells by 22-37%. Similarly, MPM triglyceride content and triglyceride biosynthesis rate were both significantly decreased after PJ consumption, by 16-27% and by 22-28%, respectively. Conclusion: PJ consumption antioxidative properties on mouse macrophages, but not PJ beneficial effects on macrophage cholesterol and triglyceride metabolism, are mediated via PJ-induced stimulation of macrophage PON2 expression. Serum PON1 stimulation by PJ consumption, however, was not involved in PJ-induced effects on macrophages. © 2010 Elsevier Ireland Ltd. Source


Koren-Gluzer M.,The Rappaport Family Institute for Research in the Medical science | Aviram M.,The Rappaport Family Institute for Research in the Medical science | Hayek T.,The Rappaport Family Institute for Research in the Medical science
Biochemical and Biophysical Research Communications | Year: 2013

The aim of the present study was to analyze the metformin (MF) effect on two cellular atherogenic activities: cholesterol biosynthesis and oxidative-stress (OS) as studied in J774A.1 macrophage cell line. MF (2-5. mM) significantly and dose-dependently reduced macrophage cholesterol content and cholesterol biosynthesis rate from acetate, but not from mevalonate, by up to 68% and 71%, respectively. MF inhibitory effect on cholesterol biosynthesis was similar to that of simvastatin. In contrast to the above anti-atherogenic MF effect, MF significantly increased cellular OS as shown by enhancement of reactive oxygen species (ROS) production by up to 70%, and decrement in cellular reduced glutathione (GSH) levels by up to 67%. Macrophage paraoxonase2 (PON2) expression however, increased by MF, by up to 1.5 folds. To overcome the MF oxidation stimulation, macrophages were incubated with MF together with potent dietary antioxidants, i.e. -5. μg GAE/ml of pomegranate juice (PJ) or 30. μM of vitamin E (VE). Both of these potent antioxidants substantially reduced MF-induced OS, and in parallel, abolished MF inhibitory effect on cholesterol biosynthesis rate. We thus conclude that the inhibition of macrophage cholesterol biosynthesis by MF is related, at least in part, to MF-induced OS. © 2013 Elsevier Inc. Source


Rosenblat M.,The Rappaport Family Institute for Research in the Medical science | Volkova N.,The Rappaport Family Institute for Research in the Medical science | Aviram M.,The Rappaport Family Institute for Research in the Medical science
BioFactors | Year: 2011

We analyzed, for the first time, the effects of recombinant PON1 (rePON1) intraperitoneal injection to C57BL/6 mice on their HDL and macrophage antiatherogenic properties. Thioglycolate-treated mice were injected with either saline (Control), or rePON1 (50 μg/mouse), and 20 H post injection, their blood samples and peritoneal macrophages (MPM) were collected. A significant increase in serum and HDL-PON1 arylesterase and lactonase activities was noted. Similarly, a significant increment, by 3.8 and 2.8 fold, in MPM-PON1 arylesterase and lactonase activities, respectively, as compared to the activities in control MPM was observed. The HDL from rePON1-injected mice was resistant to oxidation by copper ions as compared to control HDL. Furthermore, enrichment of the mouse HDL with rePON1 increased its ability to induce cholesterol efflux from J774A.1 macrophage cell line, and to inhibit macrophage-mediated LDL oxidation. In MPM from rePON1-injected mice vs. control MPM, there was a significant reduction in cholesterol mass, by 42%, in association with inhibition in cellular cholesterol biosynthesis rate, by 33%, and with significant stimulation, by 65%, of human HDL-mediated cholesterol efflux from the cells. We conclude that rePON1 injection to mice improved the mice HDL and MPM antiatherogenic properties, and these effects could probably lead to attenuation of atherosclerosis development. © 2011 International Union of Biochemistry and Molecular Biology, Inc. Source


Meilin E.,The Rappaport Family Institute for Research in the Medical science | Aviram M.,The Rappaport Family Institute for Research in the Medical science | Hayek T.,The Rappaport Family Institute for Research in the Medical science
BioFactors | Year: 2011

Diabetes mellitus (DM) is a major risk factor for the development of atherosclerosis, and high-serum levels of insulin are strongly associated with type 2 DM. Atherosclerosis is characterized by lipid-laden macrophage foam cell formations, which contain substantial amount of cholesterol and triglycerides (TG). This study analyzed for the first time, the effects of insulin on TG metabolism in macrophages under normal and diabetic conditions. Mouse peritoneal macrophages from C57BL6 mice were cultured under normal (5 mM) or high (diabetic condition, 25 mM) glucose concentration, with or without insulin, followed by the assessment of TGs metabolism in these cells. Under diabetic condition, insulin increased TG accumulation in macrophages by 100%, decreased cellular TG degradation by 21%, and increased C-reactive protein levels in macrophages by 83%. Insulin decreased hormone-sensitive lipase mRNA and protein expression by 28 and 60%, respectively, and adipose TG lipase (ATGL) protein expression by 36%, with no significant reduction in ATGL mRNA levels. The inhibition of insulin-mediated phosphorylation, and the addition of cyclic adenosine 3'5'-monoposphate, abolished the insulin-mediated inhibition of TGs degradation in cells. Insulin increases macrophage TGs accumulation only under diabetic conditions, suggesting that impaired glycemic control in diabetic patients treated with insulin may contribute to foam cell formations and enhanced inflammation in macrophages. © 2011 International Union of Biochemistry and Molecular Biology, Inc. Source


Aharoni S.,The Rappaport Family Institute for Research in the Medical science | Lati Y.,The Rappaport Family Institute for Research in the Medical science | Aviram M.,The Rappaport Family Institute for Research in the Medical science | Fuhrman B.,The Rappaport Family Institute for Research in the Medical science
BioFactors | Year: 2015

It was documented that pomegranate has anti-inflammatory effects. In this study, we investigated a direct effect of pomegranate juice (PJ) and its polyphenols on macrophage inflammatory phenotype. In vitro, PJ and its major polyphenols dose-dependently attenuated macrophage response to M1 proinflammatory activation in J774.A1 macrophage-like cell line. This was evidenced by a significant decrease in TNFα and IL-6 secretion in response to stimulation by IFNγ and Lipopolysaccharide. In addition, PJ and punicalagin dose-dependently promoted the macrophages toward a M2 anti-inflammatory phenotype, as determined by a significant increase in the spontaneous secretion of IL-10. In mice, supplementation with dietary PJ substantially inhibited the M2 to M1macrophage phenotypic shift associated with age, toward a favorable anti-inflammatory M2 phenotype. This effect was also reflected in the mice atherosclerotic plaques, as evaluated by the distinct expression of arginase isoforms. PJ consumption inhibited the increment of arginase II (Arg II, M1) mRNA expression during aging, and maintained the levels of Arg I (M2) expression similar to those in young mice aorta. This study demonstrates, for the first time, that pomegranate polyphenols directly suppress macrophage inflammatory responses and promote M1 to M2 switch in macrophage phenotype. Furthermore, this study indicates that PJ consumption may inhibit the progressive proinflammatory state in the aorta along atherosclerosis development with aging, due to a switch in macrophage phenotype from proinflammatory M1to anti-inflammatory M2. © 2015 International Union of Biochemistry and Molecular Biology. Source

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